Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide

ABSTRACT

Compound I is currently in clinical trials for the treatment of auto-immune and auto-inflammatory diseases such as psoriasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/478,789, filed Mar. 30, 2017, the disclosure of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The invention generally relates to a process for the preparation of6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide,a Tyk2 inhibitor currently in clinical trials for the treatment ofauto-immune and auto-inflammatory diseases such as psoriasis, as well asnovel intermediates used in the process.

BACKGROUND OF THE INVENTION

There is disclosed a process for the preparation of6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide,of formula I:

Compound I, compositions comprising Compound I, and methods of usingCompound I are disclosed in U.S. Pat. No. 9,505,748 B2, which isassigned to the present assignee and is incorporated herein by referencein its entirety.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a process for preparingCompound I of the formula:

comprising the steps ofa) reacting compound 1a of the formula,

where R is C₁-C₆ alkyl or aryl;with activating reagents to afford Compound 2a of the formula,

where X₁ and X₂ are independently halide or sulfonate; and R is definedas above,b) subsequently reacting Compound 2a with an aqueous base to affordCompound 3a of the formula,

where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and X₁ and X₂ are as definedabove,c) reacting Compound 3a, with Compound 7 of the formula

in a suitable solvent, and optionally in the presence of an acid, abase, or metal salts to afford Compound 8a of the formula,

where M and X₂ are defined as above,d) reacting Compound 8a with Compound 10 of the formula

in the presence of a suitable transition metal catalyst, a ligand, oneor more bases, and one or more suitable solvents to afford Compound 9aof the formula,

where M is defined as above,e) reacting Compound 9a with Compound 13 (free base or salts thereof) ofthe formula

D₃C—NH₂   Compound 13

in the presence of one or more suitable activators, one or more suitablesolvents, and optionally a base, to afford final product Compound I.

In a second aspect, the invention provides a process for preparingCompound I of the formula:

comprising the steps ofa) reacting a compound 1 of the formula

with POCl₃ and optionally an amine base, followed optionally by abuffered aqueous workup to afford Compound 2 of the formula

b) subsequently reacting Compound 2 with LiBr and DiPEA in water andacetonitrile to afford Compound 3 of the formula

c) reacting Compound 3, with Compound 7 of the formula

in the presence of zinc acetate in water and 2-propanol, to affordCompound 8 of the formula,

or a hydrate or solvate thereof;d) reacting Compound 8 with Compound 10 of the formula

in a palladium catalyzed C—N coupling reaction in the presence of aphosphine ligand, and base, using a dual-base system comprised ofpotassium carbonate and DBU, followed optionally by isolation fromaqueous acetic acid, to afford Compound 9 of the formula

or a hydrate or solvate thereof;e) reacting Compound 9 with EDC or other coupling agents and Compound 13of the formula

CD₃NH₂HCl   Compound 13

to afford final product Compound I, which may be further purified bycrystallization from NMP/IPA.

In a third aspect of the invention, there is provided a process ofpreparing Compound 7 of the formula

comprisinga) reacting compound 4a of the formula

where X₃ is Cl, Br, I or F;with N-methyl-N-formylhydrazine and a suitable base to afford Compound5a of the formula

where X₃ is defined as aboveb) which is then nitrated to afford Compound 6a of the formula

where X₃ is defined as abovec) which is subsequently reduced to afford Compound 7.

In a fourth aspect of the invention, there is provided a process ofpreparing Compound 7 of the formula

comprisinga) reacting compound 4 of the formula

with N-methyl-N-formylhydrazine in the presence of potassiumtert-butoxide to afford Compound 5 of the formula

b) which is then reacted with nitric acid in the presence ofconcentrated sulfuric acid to afford Compound 6 of the formula

c) which is subsequently reacted with hydrogen gas in the presence ofPd/C, sodium bicarbonate or sodium carbonate and methanol to affordCompound 7.

In a 5th aspect of the invention, there is provided a general process ofpreparing Compound 13 of the formula

CD₃NH₂   Compound 13

comprising

a) reacting d4-methanol of the formula

CD₃OD

with activating reagents to afford compound 11 a of the formula:

CD₃X₄   Compound 11a

where X₄ is independently halide or sulfonate,b) which is then reacted with sodium diformylamide to afford Compound 12of the formula

c) which is then hydrolyzed to afford Compound 13 of the formula

CD₃NH₂   Compound 13

Compound 13 can be isolated as the free base, or as an HCl or HBr salt.

In a 6th aspect of the invention, there is provided a process ofpreparing Compound 13 of the formula

CD₃NH₂   Compound 13

comprising

a) reacting d4-methanol of the formula

CD₃OD

with tosyl chloride in the presence of aqueous sodium hydroxide toafford compound 11 of the formula:

CD₃OTs   Compound 11

b) which is then reacted with sodium diformylamide to afford Compound 12of the formula

c) which is then hydrolyzed in the presence of hydrochloride in methanolto afford Compound 13 (as hydrochloride salt) of the formula

CD₃NH₂HCl   Compound 13.

In a 7th aspect of the invention, there are provided novel intermediatesidentified above as Compounds 5, 6, 8, 9 and 12.

In an 8th aspect of the invention, there are provided compound 3, 5, 8and 9 of the formula as its salt or hydrate form. In particular,

Another aspect of the invention provides Compound I prepared by theprocess of claim 1.

A final aspect of the invention provides a method for treatingauto-immune and auto-inflammatory diseases such as psoriasis comprisingadministering to a mammalian species, preferably a human, in needthereof, a therapeutically effective amount of Compound I, whereinCompound I is prepared utilizing the novel process steps of theinvention.

The processes of the invention have several important advantages overprior syntheses of Compound I. In particular, due to the short sequenceof chemical steps, high yields and process improvement, the throughput,cycle-time, and overall yield have been dramatically improved.Additionally, the process consistently provides Compound I in highquality for use as a pharmaceutical API.

For the conversion of Compound 8(a) to Compound 9(a), the processes ofthe first and second aspects are conducted in the presence of apalladium catalyst. Preferred palladium catalysts include, but are notlimited to Pd(OAc)₂, PdCl₂(MeCN)₂, Pd₂(dba)₃, Pd(dba)₂, [(Allyl)PdCl]₂,[(Crotyl)PdCl]₂.

The processes of the first and second aspects are also conducted in thepresence of a ligand. Preferred ligands include, but are not limited tophosphine ligands such as SL-J009-1, SL-J009-2, SL-J002-1, SL-J002-2,DPEphos, Xantphos, DPPF, DCyPF, BINAP, or derivatives thereof.

The processes of the first and second aspects are also conducted in thepresence of a base. Preferred bases include, but are not limited to,K₂CO₃, K₃PO₄, Cs₂CO₃, DBU, DBN, TMG, or combinations thereof,particularly DBU/K₂CO₃.

DETAILED DESCRIPTION OF THE INVENTION

The following schemes illustrate the improved synthetic steps of theinvention. These Schemes are illustrative and are not meant to limit thepossible techniques one skilled in the art may use to manufacturecompounds disclosed herein.

As shown below in Scheme 1, the general preparation of compound I isdescribed. Compound 1a is reacted with an activating reagent to give4,6-diactivatedpyridazine Compound 2a. Ester hydrolysis occurs in thepresence of a base to generate compound 3a as carboxylic acid or itssalt form. Compound 3a can be selectively substituted at C₄ positionwith compound 7 through contact with an appropriate acid, base or metalsalt, or under neutral conditions in the absence of any additives,yielding Compound 8a. Compound 8a can be isolated as its free form, oroptionally as a salt with an appropriate base. Compound 8a, in thepresence of a metal, an appropriate ligand, and a base, will undergo acoupling process with compound 10 to form Compound 9a. Lastly, thecoupling of compound 9a with compound 13 occurs in the presence of anactivating reagent and an optional base generates compound I.

As shown below in Scheme 2, the preparation of Compound I is described.Diethyl 1,3-acetonedicarboxylate is sequentially treated with4-acetamidobenzenesulfonyl azide and Hunig's base, tributylphosphine andwater, and acetic acid, to generate Ethyl4,6-dihydroxypyridazine-3-carboxylate (Compound 1). Chlorodehydrationwith phosphorus oxychloride affords the corresponding dichloride(Compound 2), which undergoes hydrolysis in the presence of lithiumbromide and Hunig's base in aqueous acetonitrile to yield the lithiumcarboxylate (Compound 3). Nucleophilic aromatic substitution withcompound 7 takes place at C₄ position of compound 3, in the presence ofzinc acetate, leading to the formation of compound 8 as a zinc salt.Subsequent coupling with compound 10 is catalyzed by palladium acetateand a Josiphos ligand to generate compound 9. Finally, compound 9undergoes an amidation with compound 13 in the presence of EDC, HOBt andNMI, affording compound I.

Another process of the invention is disclosed in Scheme 3 shown below.The general preparation of compound 7 is described. A cyclocondensationof compound 4a with N-methyl-N-formylhydrazine affords compound 5a,which undergoes nitration to give compound 6a. Reduction then deliversthe corresponding compound 7.

As shown below in Scheme 4, the preparation of Compound 7 is described.Compound 4 reacts with N-methyl-N-formylhydrazine in the presence ofpotassium tert-butoxide to give compound 5. Treatment of compound 5 withnitric acid and concentrated sulfuric acid delivers compound 6, whichreacts with hydrogen gas in the presence of Pd/C and sodium carbonate orsodium bicarbonate to give compound 7.

Another process of the invention is disclosed in Scheme 5 shown below.The general preparation of compound 13 is described. D4-methanol reactswith a suitable activating reagent to generate compound 11 a, whichundergoes displacement upon treatment of sodium diformylamide to formcompound 12. The subsequent hydrolysis generates compound 13.

As shown below in Scheme 6, the preparation of Compound 13 is described.D4-methanol reacts with tosyl chloride in the presence of aq sodiumhydroxide to give compound 11. Reaction of this compound with sodiumdiformylamide affords compound 12, which hydrolyzes in the presence ofacidic methanol to give compound 13 as it hydrochloride salt.

EXAMPLES

The invention will now be further described by the following workingexample(s), which are preferred embodiments of the invention. Alltemperatures are in degrees Celsius (° C.) unless otherwise indicated.These examples are illustrative rather than limiting and it is to beunderstood that there may be other embodiments that fall within thespirit and scope of the invention as defined by the claims appendedhereto.

For ease of reference, the following abbreviations may be used herein.

Abbreviations Abbreviation Name ACN acetonitrile AcOH acetic acid AParea percent aq. aqueous conc. concentrated DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DIPEA N,N-diisopropylethylamine(Hunig's base) EDC HCl 1-(dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride equiv. Molar Equivalents h hour(s) HOBt 1-hydroxybenzotriazole HPLC high pressure liquid chromatography IPA Isopropylalcohol min minute(s) Me methyl NaOH Sodium Hydroxide NMPn-methylpyrrolidinone NMR nuclear magnetic resonance Pd/C palladium oncarbon rt/RT room temperature sat. saturated t-BuOK Potassiumtert-butoxide THF Tetrahydrofuran TsCl p-toluenesulfonyl chloride

Example 1

To a glass lined reactor were charged toluene (0.26 Kg), sulfolane (3.4Kg), compound 1 (1.0 Kg) and POCl₃ (2.7 Kg). The crude was cooled to 0°C. Triethylamine (0.89 Kg) was charged, and the resulting crude mixturewas heated to 65° C. and aged till reaction reached completion. Thereaction mass was cooled to 5° C.

In a separate reactor, water (7.5 Kg) was charged and cooled to 5° C.The reaction mass was added slowly to the water solution, maintainingthe internal temperature below 5° C. Additional water (0.5 Kg) was usedto rinse the reactor and aid the transfer. The resulting mixture wasagitated at 5° C. for 3 hours, then extracted with MTBE three times(3×4.5 Kg). The combined organic layers were washed sequentially with aqpH 7 buffer solution (5.0 L/Kg, 15 wt % KH₂PO₄/K₂HPO₄) and water (2.5Kg). The crude was distilled under vacuum until total volume becameapproximately 3 L/Kg. ACN (2×6.3 Kg) was added followed by additionaldistillations back to ˜3 L/Kg. The crude was cooled to 20° C. to affordCompound 2 as a 30-36 wt % solution in 90-95% yield.

Example 2

ACN (2.7 Kg), lithium bromide (1.18 Kg) and water (0.65 Kg) were chargedto a glass-lined reactor at 25° C. Compound 2 crude solution preparedabove (limiting reagent) was added, followed by DIPEA (1.82 Kg). Theresulting slurry was agitated at 25° C. until reaction reachedcompletion. The product was isolated by filtration. The crude solid waswashed with ACN (1.6 Kg). The cake was dried under vacuum at 45° C.Compound 3 was isolated in 98 AP and 83% yield.

Example 3

Water (6.0 Kg, 6.0 L/Kg) and compound 7 (1.0 Kg) were charged to aglass-lined reactor at 25° C. Zinc acetate dehydrate (1.08 Kg, 1.0equiv) was added, followed by compound 3 (1.28 Kg, 1.20 equiv). Thereactor line was rinsed with 2-propanol (0.79 Kg, 1.0 L/Kg) and water(1.50 Kg, 1.50 L/Kg). The resulting homogeneous solution was heated to65° C. and aged until reaction reached completion. Water (7.0 Kg, 7.0L/Kg) was added, and the crude mixture was cooled to 20° C. and aged for30 min. The product was isolated by filtration. The crude solid waswashed sequentially with water (6.0 Kg, 6.0 L/Kg), water (6.0 Kg, 6.0L/Kg), THF (5.3 Kg, 6.0 L/Kg) and THF (5.3 Kg, 6.0 L/Kg). The cake wasdried under vacuum at 70° C. Compound 8 was isolated in 98 AP and 94%yield.

Example 4

A separate glass-lined reactor was flushed with nitrogen. Toluene (0.87Kg, 1.0 L/Kg) and MeCN (0.79 Kg, 1.0 L/Kg) were charged, followed by(2R)-1-[(1R)-1-[bis(1,1-dimethylethyl) phosphino]ethyl]-2-(dicyclohenxyphosphino)ferrocene (Josiphos SL-009-01) (14.1 g,1.0 mol %) and palladium acetate (2.9 g, 0.5 mol %). The reactor linewas rinsed with toluene (0.43 Kg, 0.5 L/Kg). The resulting pre-formedcatalyst solution was kept under nitrogen until further usage.

At 20° C., toluene (3.46 Kg, 4.0 L/Kg) and ACN (1.57 Kg, 2.0 L/Kg) werecharged to a glass-lined reactor flushed with nitrogen. Compound 8 (1.00Kg) was added, followed by DBU (0.39 kg, 1.00 equiv). The reactor linewas rinsed with toluene (0.43 Kg, 0.5 L/Kg). Compound 10 (0.54 Kg, 2.5equiv) and K₂CO₃ (325 mesh grade, 0.70 Kg, 2.0 equiv) were added to thereaction mixture, followed by toluene (1.30 Kg, 1.5 L/Kg) and ACN (0.79Kg, 1.0 L/Kg). The pre-formed catalyst solution was transferred into thereaction mixture, which was then heated to 75° C. and agitated until thereaction reached completion.

The reaction crude was cooled to 20° C. Aq. acetic acid (50 Volume %,4.0 Kg, 4.0 L/Kg) was charged slowly over the course of 1 h. Glacialacetic acid (10.5 Kg, 10.0 L/Kg) was then added. The resultinghomogeneous solution was washed twice with heptane (2×3.42 kg, 2×5.0L/Kg). The bottom aq. layer was collected and transferred to a cleanreactor. Water (5.0 Kg, 5.0 L/Kg) was added, followed by compound 9seeds (0.01 Kg, 1.0 wt %). The slurry was aged for 2 h at 20° C.Additional water (2.0 Kg, 2.0 L/Kg) was added, and the slurry wasfurther aged for 6 h. The product was isolated by filtration. The crudecake was washed with aq. ACN (50 Volume %, 4.5 Kg, 5.0 L/Kg) followed byACN (3.9 Kg, 5.0 L/Kg). The cake was dried under vacuum at 65° C.Compound 9 was isolated in 98.5AP and 84% yield.

Example 5

NMP (2.06 Kg, 2.0 L/Kg) and ACN (0.78 Kg, 1.0 L/Kg) were charged to aglass-lined reactor and agitated at 20° C. N-Methylimidazole (0.13 Kg,0.7 eq), Compound 13 (0.17 Kg, 1.2 eq) and Compound 9 (1.00 Kg) werecharged to the reaction mixture. The mixture was heated to 65° C. andaged until homogeneous. HOBt 20% wet (0.17 Kg, 0.5 eq), followed by EDCHCl (0.54 Kg, 1.4 eq) were then charged to the reaction mixture. Thereactor was rinsed with ACN (0.78 Kg, 1.0 L/Kg), then the resultingmixture was aged at 65° C. until reaction reaches completion. Thereaction was quenched by charging water (1.0 Kg, 1 L/Kg), then dilutedwith ACN (3.0 Kg, 3 L/Kg). The reaction mixture was aged at 65° C. for 1h, before cooling to 0° C., and aged for an additional 12 h at 0° C. Theproduct was isolated by filtration. The wet cake was washed with 2:1Water:ACN (2.8 Kg, 3 L/Kg) then ACN (2.4 Kg, 3 L/Kg), before dryingunder full vacuum at 65° C. Compound I was isolated in >99.5% purity and91% yield

If needed, the product can be subjected to optional recrystallization asfollows.

NMP (6.2 kg, 6.0 L/Kg) and Compound I (1.0 Kg) were charged to aglass-lined reactor. The batch was heated to 70° C. to form a paleyellow solution, which was then transferred through a polish filter to aclean vessel at 70° C. 2-Propanol (2.4 kg, 3 L/Kg) was added, followedby Compound I seeds (0.005 Kg, 0.005 Kg/Kg). After aging for 1 h,additional 2-propanol (4.8 kg, 6 L/Kg) was charged over the course of 2h (3 L/Kg/hr). The slurry was aged for 1 h at 70° C., cooled slowly to0° C. and aged for additional 12 h at 0° C. Product was isolated byfiltration. The wet cake was washed with 2-propanol (2×3.1 kg, 2×4 L/Kg)before drying under full vacuum at 65° C. Compound I was isolatedin >99.9% purity and 83% yield.

Example 6

To a glass lined reactor were charged methanol (1.6 Kg/Kg, 2.0 L/Kg) andmethyl hydrazine (1 Kg) at 0° C. Methyl formate (0.57 Kg/Kg, 1.1 equiv)was added drop-wise. The crude was warmed up to 20° C. and aged foradditional 6 h. The crude was distilled under vacuum until total volumebecame approximately 0.5 L/Kg. Five put/take distillations with 2-MeTHF(5×3.6 Kg/Kg) were undertaken for the purpose of azeotropic drying. Thecrude was cooled to 20° C. N-Methyl-N-formylhydrazine was isolated as89-90 wt % solution in 89-91% yield.

Example 7

To a glass lined reactor were charged potassium tert-butoxide (1.5Kg/Kg, 2.4 equiv) and THF (12.2 Kg/Kg) at 0° C. A mixture of compound 4(1.0 Kg), N-Methyl-N-formylhydrazine (1.0 Kg/Kg, 2.30 equiv) and THF(5.3 Kg/Kg, 6.0 L/Kg) was added slowly. The reactor line was rinsed withTHF (0.5 Kg/Kg). The reaction crude was aged at 0° C. until reactionreached completion. Water (5.0 Kg/Kg) was added, and the resultingmixture was aged at 0° C. for 30 min, heated to 40° C. and aged foradditional 30 min. The layers were separated and the aq layer discarded.The organic layer was washed with brine (15 wt %, 5.7 Kg/Kg) beforedistilling under vacuum until total volume became approximately 5 L/Kg.Four put/take distillations with ethyl acetate (4×10 L/Kg) wereundertaken for the purpose of azeotropic drying. The crude was cooled to20° C. Sulfuric acid (0.66 Kg/Kg, 1.10 equiv) was added, and the slurrywas agitated for 2-3 h. Product was isolated by filtration. The cake wasconsecutively washed with ethyl acetate (2×6.5 L/Kg) and heptane (8L/Kg), and dried under vacuum at 45° C. Compound 5 was isolated in 99 APand 83% yield.

Example 8

To a glass lined reactor were charged concentrated sulfuric acid (4.5Kg/Kg) and compound 5 (1.0 Kg) at 0-5° C. Nitric acid (68 wt %, 0.35Kg/Kg, 1.2 equiv) was added drop-wise. The mixture was agitated at 0-5°C. until reaction reached completion.

In a separate reactor, water (12 Kg/Kg) and methanol (6.5 Kg/Kg, 8.3L/Kg) were mixed well at 20° C. The nitration crude was transferredslowly into the methanol water mixture. The reactor line was rinsed withmethanol (0.5 Kg/Kg). The crude was heated to 40-45° C. Aq. ammoniumhydroxide (25 wt %, 7.4 Kg/Kg) was added slowly. The resulting slurrywas cooled to 20° C. and agitated for 3 h. Product was isolated byfiltration. The cake was washed with water (2×6 L/Kg), and dried undervacuum at 45° C. Compound 6 was isolated in 99 AP and 95% yield.

Example 9

To a high pressure reactor flushed with nitrogen were charged methanol(8.0 Kg/Kg) and compound 6 (1.0 Kg). With careful exclusion of oxygen,sodium bicarbonate (0.6 Kg/Kg, 2.0 equiv) and Pd/C (10% loading, 50%wet, 0.02 Kg/Kg) were added. The reactor was pressurized with hydrogen(41-46 psi), and the reaction mixture was aged at 20° C. for 6 h thenheated to 45° C. and aged till reaction reached completion. The reactorwas flushed with nitrogen, and the reaction crude was filtered to removePd/C. Methanol (5 Kg/Kg) was used to aid the transfer. The combinedfiltrates were distilled under vacuum until total volume becameapproximately 2.5 L/Kg. Water (10 Kg/Kg) was added, and the crude wasdistilled under vacuum until total volume became approximately 2.5 L/Kg.The crude was heated to 70° C. Brine (25 wt %, 9.0 Kg/Kg) was added, andthe resulting crude was agitated for 6 h at 70° C. After cooling down to0° C., the crude was further aged for 6 h. Product was isolated byfiltration. The cake was washed with brine (pre-cooled to 0° C., 25 wt%, 2.0 Kg/Kg), and dried under vacuum at 45° C. Compound 7 was isolatedin 99 AP and 88% yield.

Example 10

To a glass lined reactor flushed with nitrogen were charged water (16.3L/Kg) and sodium hydroxide (3.3 Kg, 3.0 equiv). The mixture was agedtill sodium hydroxide reached full dissolution. The crude was cooled to0° C. D4-Methanol (1.0 Kg) and THF (4.5 L/Kg) were charged. A solutionof TsCl (6.3 Kg, 1.2 equiv) in THF (6.3 Kg, 7.1 L/Kg) was added over thecourse of 2 h. The crude was agitated at 0° C. until reaction reachedcompletion. The batch was warmed to 20° C. The layers were separated.The collected organic layer was diluted with MTBE (4.0 Kg, 5.4 L/Kg),washed with brine twice (25 wt %, 4.0 Kg followed by 12 Kg). The organiclayer was distilled under vacuum until total volume became approximately10 L/Kg. Two put/take distillations with ACN (2×10 L/Kg) were undertakenfor the purpose of azeotropic drying. The crude was cooled to 20° C. ACN(10.0 Kg, 12.8 L/Kg) and NaN(CHO)₂ (3.3 Kg, 1.2 equiv) were added. Thecrude was heated to 65° C. and agitated until reaction reachedcompletion. After cooling down to 5° C., the mixture was filtered, andthe crude cake was washed with ACN twice (2×2.5 Kg, 2×3.2 L/Kg). Thecombined filtrates were distilled under vacuum until total volume becameapproximately 3 L/Kg. The crude was cooled to 20° C. Compound 12 wasisolated as an oil with 80-85 wt % in 60-70% yield.

Example 11

To a glass lined reactor were charged compound 12 (1.0 Kg) and methanol(3.9 Kg, 5.0 L/Kg) at 20° C. A solution of HCl in IPA (5-6 N, 4.5 Kg,1.5 equiv) was added. The resulting mixture was heated to 50° C. andagitated until reaction reached completion. THF (10 Kg, 11.2 L/Kg) wasadded slowly and the crude was cooled to 0° C. over 2 h to afford aslurry. The product was isolated by filtration. The cake was washed withTHF (3.7 Kg, 4.1 L/Kg), and dried under vacuum at 45° C. Compound 13 wasisolated in 80% yield.

If needed, the product can be subjected to optional recrystallization asfollows. Methanol (5.6 Kg, 8.3 L/Kg) and Compound 13 (1.0 Kg) werecharged to a glass-lined reactor. DBU (0.1 Kg) was added slowly. Thecrude was agitated for 1 h. THF (12.4 Kg, 13.9 L/Kg) was added slowly,and the resulting slurry was aged for 2 h. The product was isolated byfiltration. The cake was washed with THF (2.6 Kg, 2.9 L/Kg), and driedunder vacuum at 45° C. Compound 13 was isolated in 60% yield (1st crop).The mother liquor was distilled under vacuum until total volume becameapproximately 1 L/Kg. Two put/take distillations with methanol (2×2.8Kg, 2×3.6 L/Kg) were performed and the solution was concentrated back to˜1 L/Kg. The crude was cooled to 20° C. THF (4.8 Kg, 5.4 L/Kg) wasadded, and the resulting slurry was aged for 2 h. The product wasisolated by filtration. The cake was washed with THF (1.0 Kg), and driedunder vacuum at 45° C. Compound 13 was isolated in 25% yield (2nd crop).

What is claimed is:
 1. A process for preparing Compound 7 of the formula

comprising b) reacting compound 4a of the formula

where X₃ is Cl, Br, I or F; with N-methyl-N-formylhydrazine and asuitable base to afford Compound 5a of the formula

b) which is then nitrated to afford Compound 6a of the formula

c) which is subsequently reduced to afford Compound
 7. 2. A process forpreparing Compound 7 of the formula

comprising a) reacting compound 4 of the formula

with N-methyl-N-formylhydrazine in the presence of potassiumtert-butoxide to afford Compound 5 of the formula

b) which is then reacted with nitric acid in the presence ofconcentrated sulfuric acid to afford Compound 6 of the formula

c) which is subsequently reacted with hydrogen gas in the presence ofPd/C, sodium bicarbonate or sodium carbonate and methanol to affordCompound
 7. 3. A process for preparing Compound 13 of the formulaCD₃NH₂ or a salt thereof, comprising a) reacting d4-methanol of theformulaCD₃OD with activating reagents to afford compound 11a of the formula:CD₃X₄   Compound 11a where X₄ is independently halide or sulfonate, b)which is then reacted with sodium diformylamide to afford Compound 12 ofthe formula

c) which is then hydrolyzed to afford Compound
 13. 4. A process forpreparing Compound 13 of the formulaCD₃NH₂   Compound 13 comprising a) reacting d4-methanol of the formulaCD₃OD with tosyl chloride in the presence of aqueous sodium hydroxide toafford compound 11 of the formula:CD₃OTs   Compound 11 b) which is then reacted with sodium diformylamideto afford Compound 12 of the formula

c) which is then hydrolyzed in the presence of hydrochloride in methanolto afford Compound 13 as its hydrochloride salt of the formulaCD₃NH₂HCl   Compound
 13. 5. A compound selected from the following

or a salt or hydrate thereof.
 6. A compound according to claim 5 whichis

or a hydrate thereof.
 7. A compound according to claim 5 which is

or a hydrate thereof.
 8. A compound according to claim 5 which is


9. A compound of the formula


10. Compound I of the formula

prepared by a process comprising the steps of a) reacting compound 1a ofthe formula,

where R is C₁-C₆ alkyl or aryl; with activating reagents to affordCompound 2a of the formula,

where X₁ and X₂ are independently halide or sulfonate; and R is definedas above, b) subsequently reacting Compound 2a with an aqueous base toafford Compound 3a of the formula,

where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and X₁ and X₂ are as definedabove, c) reacting Compound 3a, with Compound 7 of the formula

in a suitable solvent, and optionally in the presence of an acid, abase, or metal salts to afford Compound 8a of the formula,

where M and X₂ are defined as above, d) reacting Compound 8a withCompound 10 of the formula

in the presence of a suitable transition metal catalyst, a ligand, oneor more bases, and one or more suitable solvents to afford Compound 9aof the formula,

where M is defined as above, e) reacting Compound 9a with Compound 13,or a free base or salt thereof, of the formulaD₃C—NH₂   Compound 13 in the presence of one or more suitableactivators, one or more suitable solvents, and optionally a base, toafford Compound I.